Pharmacology 3 antimalarial drugs lecture 11 by Prof.Dr. Mohamed Fahmy

Malaria Caused by four species of the plasmodia which are protozoa These are Plasmodium falciparum, P vivax, P malariae & P ovale P falciparum is the most dangerous (can lead to fatal cerebral malaria)

Life cycle 1- Asexual cycle a- Exoerythrocytic stage Anopheles female mosquito inject saliva containing sporozoites into human Sporozoites infect liver & developed into schizonts which release merozoites into blood b- Erythrocytic stage Merozoites infect RBCs & multiply RBCs rupture & release merozoites that destroy more RBCs (clinical symptoms)

2- Sexual cycle Some merozoites differentiates into gametocytes (male & female) which are taken up by mosquito to begin another cycle Note In P vivax & P ovale a dormant stage (hypnozoites) can remain in the liver & causes relapses by invading the blood stream weeks or even years later

Sites of action of antimalarial drugs 1- Tissue schizonticides Prevent relapse e.g., Primaquine 2- Blood schizonticides Terminate clinical attack e.g., Chloroquine, Quinine, Mefloquine, Proguanil, Pyremethamine & tetracycline 3- Gametocyticides Prevent transmission e.g., Primaquine, Proguanil & Pyremethamine

Antimalarial drugs 1- Primaquine It is a tissue schizonticide & gametocide Mechanism of action Acts by generating reactive oxygen species or by interfering with respiratory chain in parasite Therapeutic uses 1- Radical cure of relapsing malaria 2- Prevent transmission of P falciparum Adverse effects GIT disturbances & bone marrow depression Hemolytic anemia in patients with G6PD deficiency

2- Chloroquine (Cidoquine, Alexoquine) It is a blood schizonticide Mechanism of action 1- Inhibits the digestion of hemoglobin by parasite ( pH) synthesis of amino acids 2- Inhibits polymerase enzyme which converts heme (toxic) into hemozoin (non toxic) 3- The accumulation of heme results in lysis of the parasite

Therapeutic uses Treatment & prophylaxis against all types of plasmodium except for P falciparum Resistance Chloroquine resistant parasites are able to expel the drug via P-glycoprotein pump Adverse effects 1- Low doses GIT disturbances, skin rash, headache & blurred vision 2- High doses Retinopathy, ototoxicity & myocardial depression

3- Quinine An alkaloid derived from cinchona bark Blood schizonticidal drug Has no effect on liver stages of plasmodium Mechanism of action Inhibits heme polymerase with accumulation of toxic heme Forms complex with parasite DNA Therapeutic uses Drug of choice for treatment of acute P falciparum

Side effects Cinchonism Headache, nausea, blurred vision, tinnitus & vertigo Hypotension & myocardial depression Has oxytocic effect (contraindicated in pregnancy)

4- Mefloquine (Lariam) Chemically related to quinine Very potent with a long half-life (17 days) Acts by forming toxic complex with free heme that damages parasite membrane Used only in P falciparum resistant to chloroquine May cause fetal abnormalities (contraindicated in pregnancy)

5- Proguanil &Pyremethamine Mechanism of action Inhibit malarial dihydrofolate reductase enzyme prevent formation of tetrahydrofolate inhibits DNA synthesis & cell division The combination of pyremethamine with sulfadoxine (Fansidar) has a synergistic effect through blocking 2 steps in folic acid synthesis

Therapeutic uses Fansidar is used in the treatment of chloroquine-resistant P falciparum Adverse effects Proguanil Mouth ulcer & stomatitis Pyremethamine Megaloblastic anemia & skin rash

6- Artemisinin derivatives Isolated from the leaves of artemisia (Chinese herb) Examples include Artesunate, Artemether & Arteether These componds generate free radicals that oxidize proteins & lipids leading to parasite death They are effective blood schizonticides against all types of malaria

7- Antibiotics Some antibiotics in addition to sulfonamides are active against malaria The mechanism of action of these drugs are unclear Examples: - Tetracycline & doxycycline - Clindamycin - Azithromycin or fluoroquinolones